New pharmaceutical compositions having anti-psychotic properties

Description

[0001] The invention relates to the use of piperazine derivatives for the manufacture of pharmaceutical compositions having interesting psychotropic properties, notably anti-psychotic properties, to new bicyclic heteroaryl piperazine derivatives which can be used in such compositions as the active substance and to the preparation of these compositions and compounds.

[0002] It was found that compounds of the general formula 1

in which

[0003] A together with the two carbon atoms of the phenyl group forms an entirely or partly unsaturated cyclic group having 5-7 ring atoms with in the ring 1-3 hetero atoms from the group 0, S and N, with the proviso that the sum of the number of oxygen atoms and sulphur atoms is at most 2, and that the nitrogen atoms in the ring may be substituted with a group R4 which may be hydrogen, alkyl, hydroxyalkyl or acyl;

[0004] B is an optionally branched or cyclic, saturated or (poly)unsaturated aliphatic chain which may comprise one or more atoms from the group O and N in the chain or terminally and in which carbonyl groups, thiocarbonyl groups, sulphinyl groups or sulphonyl groups may also be present; the chain may moreover be substituted with one or more halogen atoms or with one or more optionally substituted phenyl groups, heteroaryl groups or heterocyclic groups; if the chain comprises a nitrogen atom, this is substituted with at least one group R5 which is an optionally substituted phenyl group or an alkyl group, cycloalkyl group, hydroxyalkyl group;

[0005] R1 and R2 may be alkyl, cycloalkyl, optionally substituted phenyl or heteroaryl, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, mono- or dialkylamino, mono- or diarylamino, hydroxyl, amino, alkyl-, alkoxy- or amino, or mono- or dialkylaminocarbonyl, nitro, cyano, halogen, trifluoromethyl, trifluoromethoxy, alkyl- or amino- or mono- or dialkylaminosulphonyl; R2 may moreover be an oxo group or thioxo group; m has the value 0-3 and p has the value 0-2; and

[0006] R3 is an alkyl group and n has the value 0-2, and the acid addition salts thereof can be used for the manufacture of medicaments having psychotropic activity.

[0007] Based on their properties the use of compounds of formula 1, in which the symbols have the following meanings, and the salts thereof is to be preferred:

[0008] A forms together with the two carbon atoms of the phenyl group an entirely or partly unsaturated ring consisting of 5-atoms, which ring comprises at least one oxygen atom;

[0009] B is straight, branched or cyclic alkyl, alkenyl, alkynyl, alkoxy- or hydroxyalkyl, aryl- or heteroarylalkyl, or a group of the formula ―D―NR5―CO―R6, in which D is an optionally branched alkyl chain having at most 8 carbon atoms, R5 has the above meaning, and R6 is alkyl, cycloalkyl, a phenyl group substituted with a group R1, in which R1 has the above-mentioned meaning, a saturated or non-saturated heterocyclic group, or R5 and R6 together with the group ­NR5­CO­ form a heterocyclic system;

[0010] R1 and R2 are alkyl, alkoxy, hydroxyl, nitro, cyano, halogen, trifluoromethyl, on the understanding that R1 is in the meta- and/or para-position in relation to the piperazine group;

m and p have the value 0-2; and

n is 0.

[0011] When R1―R6 is or comprises an alkyl group, this is preferably a straight or branched alkyl group having 1-5 carbon atoms.

[0012] As a cycloalkyl group, the groups R1, R2, R5 and R6 comprise a ring system having 3-7 ring atoms and not more than 10 carbon atoms as a whole. When R1, R2, R4 or R5 is a hydroxyalkyl group, such a group preferably comprises 1-5 carbon atoms. As a halogen atom, R1, R2 preferably is fluorine, chlorine or bromine. Optionally present hydroxyl or hydroxyalkyl groups may be esterified or etherified.

[0013] Compounds which use is to be preferred in particular on the basis of their properties are:

a) 1-(benzo[b]furan-7-yl)-4-methylpiperazine;

b) 1-[4-fluoro(benzo[b]furan-7-yl)]-4-methylpiperazine;

c) 1-[5-fluoro(benzo[b]furan-7-yl)]-4-methylpiperazine;

d) 1-(benzo[b]furan-7-yl)-4-(2-hydroxyethyl)piperazine;

e) 1-(benzo[b]furan-7-yl)-4-propylpiperazine;

f) 1-(benzo[b]furan-7-yl)-4-isopropylpiperazine;

g) 1-[5-fluoro(benzo[b]furan-7-yl)]-4-isopropylpiperazine;

h) 1-(benzdioxol-4-yl)-4-isopropylpiperazine;

i) 1-(benzo[b]furan-7-yl)-4-allylpiperazine;

j) 1-(benzo[b]furan-7-yl)-4-propargylpiperazine;

k) 1-[4-fluoro(benzo[b]furan-7-yl)]-4-propargylpiperazine;

I) 1-(benzdioxol-4-yl)-4-propargylpiperazine;

m) I-(benzo[b]furan-7-yl)-4-isobutylpiperazine;

n) 1-(benzo[b]furan-7-yl)-4-cyclopropylmethylpiperazine;

o) 1-(benzo[b]furan-7-yl)-4-pentylpiperazine;

p) 1-(benzo[b]furan-7-yl)-4-[2-(2-furyl)ethyl]piperazine;

q) 1-(benzo[b]furan-7-yl)-4-(4-chlorobenzyl)piperazine;

r) 1-(benzo[b]furan-7-yl)-4-(2-phenylethyl)piperazine;

s) 1-(benzo[b]furan-7-yl)-4-[2-[N-(acetyl)-N-(methyl)amino]ethyl]piperazine;

t) 1-(benzo[b]furan-7-yl)-4-[2-[N-(pyrrolidin-2-onyl)]ethyl]piperazine;

u) 1-(benzo[b]furan-7-yl)-4-[2-(N-succinimidyl)ethyl]piperazine;

v) 1-(benzo[b]furan-7-yl)4-[2-[N-(oxazolidin-2-onyl)ethyl]]piperazine;

w) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-chlorobenzoyl)-N-(methyl)amino]ethyl]piperazine;

x) 1-benzo[b]furan-7-yl)-4-[2-[N-(4-cyanobenzoyl)-N-(methylamino)ethyl]piperazine;

y) I-(benzo[b]furan-7-yl)-4-[2-[N-(4-nitrobenzoyl)-N-(methyl)amino]ethyl]piperazine;

z) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-methoxybenzoyl)-N-(methyl)amino]ethyl]piperazine;

aa) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-(methyl)amino]ethyl]piperazine;

bb) 1-[4-fluoro(benzo[b]furan-7-yl)]-4-[2-[N-(4-isopropylbenzoyl)-N-(methyl)amino]ethyl]piperazine;

cc) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl-N-(2-hydroxyethyl)amino]ethyl]piperazine;

dd) I-(benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-propyl)amino]ethyl]piperazine;

ee) 1-(benzo[b]furan-7-yl)-4-[[N-methyl-5-(4-fluorophenyl)pyrrol-2-yl]methyl]piperazine;

ff) I-(benzo[b]furan-7-yl)-4-(acetylmethyl)piperazine.

[0014] Suitable acids with which the compounds according to the invention can form pharmaceutically acceptable acid addition salts are, for example, hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluenesulphonic acid, methanesulphonic acid, naphtalenesulphonic acid and the like.

[0015] When a centre of chirality is present, both the racemate and the individual enantiomers belong to the invention. The compounds according to the invention have interesting psychotropic properties and may hence be used for the treatment of affections and diseases which are the result of disturbances in the central nervous system, for example psychoses, aggression, fear and depression.

[0016] The compounds notably have a specific antipsychotic activity which is not associated with the side effects as a result of dopaminolytic and sedative activities which generally are to be considered as undesired.

[0017] The antipsychotic activity was determined in a test procedure in which the suppression of conditioned behaviour in experimental animals (rats) was measured in a manner known per se. The compounds were evaluated as active when in this test they show at least 50% suppression of the conditioned behaviour after oral administration of 50 mg per kg of body weight or less.

[0018] The dopaminolytic activity of the compounds was determined by means of behavioural or biochemical tests known per se, for example, induction of catalepsy, increase of the dopamine synthesis or conversion rate in the central nervous system, and by affinity to dopamine receptors which is determined by displacement of a radioactive labelled ligand in a tissue homogenate.

[0019] The sedative activity of the compounds was measured in a test in which their influence upon the spontaneous locomotoric activity of experimental animals is determined according to methods known per se.

[0020] It was found that the dopaminolytic and sedative side effects as a rule do not occur with dosages which are at least three times as high as those in which 50% suppression of the conditioned behaviour is found.

[0021] The quantity, frequency and way of administration may differ for each individual case, also dependent on the nature and the severity of the disturbances. In general, a dosage of 1-500 mg per day, and preferably 1-100 mg daily, may be used for humane applications in one dosage per day.

[0022] The active compounds according to the invention and their salts and prodrug forms can be processed to compositions by means of standard methods which are known per se, for example, pills, tablets, coated tablets, capsules, powders, injection liquids and the like, while using the usual auxiliary substances, for example, solid and liquid carrier materials.

[0023] The compounds and their acid addition salts, and enantiomers can be brought into a form suitable for administration in a manner known perse. The compounds of the formula (1) are new compounds with the exception of the compounds wherein A forms together with the two carbon atoms of the phenyl group a completely are partly unsaturated 5- or 6-membered ring which contains a nitrogen atom in the meta- or ortho-position in relation to the piperazine group as the only hetero atom, R1 is halogen, nitro or lower alkoxy, R2 is lower alkyl or an oxo group, n is 0, p is 0 or 1, m has the value 0-2, and B has the above mentioned meaning, which compounds are partly known from French patent specification 81,23744, Japanese patent specification 57,193459, British patent specification 2,086,896 and/or J. Chem. Soc., C, no. 10 (1967), pages 1003-1006. The new compounds according to the invention can be prepared in a manner known for the synthesis of analogous compounds, for example, as described in Netherlands Patent Application 8005133.

[0024] Some related compounds are described in US-A-3 808 212, Coll. Czech. Chem. Commun. 40,1975, pp. 1612-1622, and EP―A―48085.

[0025] The compounds can be obtained more in particular by reaction of a compound of formula 2

with a compound of formula L-B, in which A, B, R₁―R₃, m, n and p have the meanings mentioned hereinbefore, and L is a so-called leaving group, for example hydroxyl, chlorine, bromine or tosylate. This reaction may be carried out both with and without an aprotic organic solvent, optionally in the presence of an acid binder. Examples of suitable solvents are methyl ethyl ketone, tetrahydrofuran, acetonitril, dimethyl formamide, toluene and petroleum ether. As acid binders are to be considered substances can either be soluble or unsoluble in the reaction medium, for example, organic nitrogen bases, such as trialkyl amines, pyridine, urea, and inorganic bases, such as sodium or potassium carbonate or -bicarbonate. The reaction temperature usually is between room temperature and the reflux temperature of the solvent used, while the reaction duration may vary from 1 to 20 hours.

[0026] Further the compounds of the invention of the formula (1) can be obtained by reaction of a compound of the above formula (2) with a carbonyl compound of the formula B'=O under the influence of a gentle reducing agent. In these formulae A, R₁-C₃, m, n and p have the above meaning and B'=O results after the reaction in a group B having the above meaning. This method is suitable in particular for the preparation of compounds of formula (1) wherein B represents a branched alkyl group or cycloalkyl group. The reaction is preferably carried out in an alcoholic solvent in the presence of a reduction agent which does not react with the carbonyl group, such as metal borohydride, preferably sodium cyanoborohydride. The reaction temperature is usually between 0°C and reflux temperature. The reaction time varies from a few minutes to several hours.

[0027] In so far as the starting compounds of formula 2 are new, they can be obtained according to methods which are known for the synthesis of analogous compounds, for example, according to methods which are known from Netherlands Patent Applications 80.05133 and 82.01708.

[0028] The compounds of formula 1 in which A, R₁-R₃, m, n and p have the above-mentioned meanings and B is a group of the formula D―NR₅―CO―R₆, in which D, R₅ and R₆ have the above-mentioned meanings, with the proviso that R₅ is not a phenyl group, are preferably prepared from the corresponding compound of formula 3,

by converting this with a compound L-R₅, in which A, R₁-R₃, D, L, R₅, R_e, m, n and p have the above-mentioned meanings. This reaction is preferably carried out in two steps. In the first step the proton of the nitrogen atom of the compound of formula 3 is removed by means of a strong organic base, for example, sodium hydride, potassium hydride or calcium hydride, or a sodium alkoxylate or potassium alkoxylate, preferably tert. butylate, in an aprotic organic solvent, for example, toluene, tetrahydrofuran, dimethylformamide or dimethylsulphoxide, at temperatures between -20°C and the reflux temperature of the solvent. In the second step the reagent L-R₅ is added to the reaction mixture, the desired final product being usually obtained after a reaction time which varies from 5 minutes to a few hours.

[0029] A similar process can be used to convert compounds of the formula 3, wherein the group -NH- is replaced by a group -CH₂-, and the other symbols have the above mentioned meanings.

[0030] These compounds in which A, R₁―R₃, m, n and p have the above-mentioned meanings and B is a group of the formula D―NR₅―CO―R₆, in which D, R₅ and R₆ have the above-mentioned meanings, may moreover be prepared from the corresponding compounds of formula 4,

by converting them with a compound E-CO-R₆, in which A, R₁―R₃, D, R₅, R₆, m, n and p have the above-mentioned meanings and E is a leaving group, preferably of the type hydroxy, alkoxy, acyloxy, halogen, N-imidazolyl or N-triazolyl. This reaction is preferably carried out in an aprotic organic solvent, for example, those mentioned hereinbefore, in the presence of an acid binder, as mentioned hereinbefore, at temperatures between 0°C and the reflux temperature of the solvent used and a reaction duration which may vary from 5 minutes to a few hours.

[0031] A further suitable method for preparing some compounds of the formula (1) is reduction of a compound of the formula 1 wherein A, B, R₁-R₃, n, m and p have the above meanings on the understanding that B contains a carbonyl group directly attached to the piperazine nitrogen atom. This reaction can be carried out with reducing agents such as LiALH₄ or a borane-complex like BH₃.dimethyl- sulphide, in a suitable solvent, for example diethyl ether or tetrahydrofuran, at temperatures between 0°C and the reflux temperature of the solvent used. The reaction time is usually several hours.

[0032] In so far as the starting compounds of formulae 3 and 4 are new, they can be obtained in a manner analogous to the method described hereinbefore for the preparation of compounds of formula 1, starting with a compound of formula 2.

[0033] Compounds of the formula (1) can also be obtained from precursors having formula (1) in a way known per se, for example by using hydrogenation reactions or by reactions resulting in carbon atom-hetero atom bonds in chain B via nucleophilic substitution reactions whereby the reactant containing the hetero atom functions as nucleophile.

[0034] Furthermore, some compounds of formula 1 in which at least one of the groups B, R₁, R₂, R₄ or R₅ comprises a hydroxyl function or in which B comprises an NH-R_s group, can be prepared by splitting off in the last step a protective group, for example, an acetal, ketal, acyl, triphenyl methyl, trialkylsilyl, alkoxy- or trialkylsilylethyl- oxycarbonyl, by means of methods known for the purpose.

[0035] The invention will now be described in greater detail with reference to the following specific examples.

Example I

1-benzo-[b]furan-7-yl-4[3-(4-fluorobenzoyl)propyl]piperazine HCL

[0036] 7.5 Mmol (1.79 g) of 1-benzo[b]furan-7-yl-piperazine HCI, together with 9.1 mmol (1.82 g) of 1-chloro-3-(4-fluorobenzoyl)-propane, 20 mmol (2.80 g) of potassium carbonate and a catalytic quantity (approximately 100 mg) of sodium iodide as a suspension in 50 ml of methyl ethyl ketone, was heated with thorough stirring so that the solvent refluxes. After stirring for 16 hours, 9.1 mmol of 1-chloro-3-(4-fluorobenzoyl)propane and 20 mmol of potassium carbonate were added again. After stirring for another 16 hours at reflux temperature, cooling, filtering and evaporating to dryness in vacuo were carried out. The residue was chromatographed on silica gel with ethyl acetate as an eluent. After evaporating the fractions which comprised the desired product, material was obtained which was converted into the title compound via treatment with 1 equivalent of a HCI solution in ethyl acetate.

[0037] The compounds of formula 5A or 5B recorded in Table A were prepared in an analogous manner.

Example 11

1-Benzo[b]furanl-7-yl-4-[2-[N-(4-isopropylbenzoyl)-N-(methylamino]ethyl]piperazine HCI

[0038] A suspension of 75 mmol (8.55 g) of potassium hydride in mineral oil (35% KH) was washed three times with dry petroleum ether in a reaction vessel which was kept under an atmosphere of dry nitrogen. After pipetting the last quantity of petroleum ether, 70 ml of dry dimethylsulphoxide were slowly added dropwise, hydrogen gas escaping. After 15 minutes a solution of 59.2 mmol (23.2 g) of 1-benzo[b]furan-7-yl-4-[2-[N-(4-isopropylbenzoyl)amino]ethyl]piperazine in 140 ml of dry dimethylsulphoxide was rapidly added dropwise at a temperature of 20°C. A solution of 74 mmol (4.61 g) of methyl iodide in 50 ml of dry dimethylsulphoxide was added to the resulting yellow coloured solution at such a rate that the temperature of the reaction mixture remained below 30°C. After 30 minutes the reaction mixture was poured out on water, after which extraction with ethyl acetate was carried out. After drying these extracts over magnesium sulphate, filtration and evaporation, a cloudy oil was obtained. It was taken up in approximately 800 ml of ethyl acetate and after filtration was treated with 1 equivalent of alcoholic HCI. The title compound started to crystallize out substantially immediately. After cooling, sucking off and drying, a white powder was obtained having a melting-point of 246-247°C (decomposition).

[0039] The compounds of formula 6A and B recorded in Table B hereinafter were prepared in an analogous manner.

Example III

1-(Benzo(b]furan-7-yl-4-[2-[N-(acetyl)-N-methyl)amino]ethyl]piperazine hydrochloride

[0040] 4.1 Mmol (0,62 ml) of triethylamine and 4,0 mmol (0,29 ml) of acetyl chloride were successively added to a solution of 3.7 mmol (0,96 g) of N-[2-[4-(benzo[b]furan-7-yl)-1-piperazinyl]ethyl]-N-methylamine in 50 ml of chloroform at room temperature, giving an exothermic reaction. After stirring for 15 minutes 5 ml of methanol was added and the mixture was sucked off to dryness in vacuo. The residue was treated with ether which resulted in crystallization of the obtained triethylamine hydrochloride. This was sucked off and washed with ether. The filtrate after evaporation was taken up in ethyl acetate. 1 Equivalent of hydrochloric acid was added, giving the title compound as a solid substance.

[0041] The compounds of formula 6A listed in table C were prepared in an analogous manner:

Example IV

1-(Benzo[b]furan-7-yl)-4-isopropylpiperazine hydrochloride

[0042] 0.36 MI of acetic acid, 0.52 g of sodium acetate and 1.0 ml of acetone were added successively to a solution of 6.28 mmol (1.50 g) of 1-(benzo[b]furan-7-y))-piperazine hydrochloride in 20 ml of methanol at room temperature. After stirring for 30 minutes at room temperature 0.38 g of sodium cyanoborohydride were added to the reaction mixture and stirring was continued for 3 hours. After evaporation in vacuo the residue was purified by means of flash-chromatography on silica gel. The fractions containing the desired product were evaporated and the so-obtained free base was converted into the crystalline title compound by treatment with 1 equivalent of HCI in ethyl acetate.

[0043] The compounds of formulae 5A and 5B indicated in table D have been prepared in an analogous manner:

Example V

1-(Benzo[b]furan-7-yl)-4-(cyclopropylmethyl)piperazine hydrochloride

[0044] 0.28 g Of lithium aluminum hydride were added in small portions to a solution of 5.8 mmol (1.56 g) of 1-(benzo[b]furan-7-yl)-4-(cyclopropylcarbonyl)piperazine in 30 ml of dry tetrahydrofuran. The mixture was stirred until the formation of gas stopped. After adding of 5 ml of water and 50 ml of 2N sodium hydroxide the reaction mixture was extracted and the organic layers were evaporated. Chromatographic purification on silica gel resulted in 1.0 g of a viscous substance, which was converted into the title compound by treatment with 1 equivalent of HCL in ethyl acetate.

[0045] The compounds of formula 5A mentioned in table E been prepared in similar way.

Example VI

1-(Benzo[b]furan-7-yl)-4-[2-[N-(pyrrolidin-2-onyl)]-ethyl]piperazine hydrochloride

[0046] A suspension of 5 mmol (0.58 g) of potassium hydride in mineral oil (35% KH) was washed three times with dry petroleum ether in a reaction vessel which was kept under an atmosphere of nitrogen. Then 5 ml of dry dimethylsulphoxide were added dropwise giving a clear solution. 4.15 Mmol (0.315 ml) of 2-pyrrolidinon was added. After stirring for 20 minutes at room temperature 3.77 mmol (1.0 g) of 1-(benzo[b]furany-7-yl)-4-(2-chloroethyl)piperazine were added to the clear solution. After stirring for 16 hours at room temperature and 1 hour at 70°C the mixture was poured out on a system of two phases consisting of water and ethylacetate. After extraction 1.10 g of an oil were obtained, which was purified by flash-chromatography on silica gel. The obtained substance (0.76 g) was converted with HCI in ethanol. The title compound was obtained after crystallization from a mixture of ethanol and ethyl acetate.

[0047] The compounds of the formula 5A mentioned in table F were prepared in a similar way:

Claims

1. Use of a compound of the formula 1

wherein:

A together with the two carbon atoms of the phenyl group forms an entirely or partly unsaturated cyclic group having 5-7 ring atoms with in the ring 1-3 hetero atoms from the group O, S and N, with the proviso that the sum of the number of oxygen atoms and sulphur atoms is at most 2, and that the nitrogen atoms in the ring may be substituted with a group R₄ which may be hydrogen, alkyl, hydroxyalkyl or acyl;

B is an optionally branched or cyclic, saturated or (poly)unsaturated aliphatic chain which may comprise one or more atoms from the group 0 and N in the chain or terminally and in which carbonyl groups, thiocarbonyl groups, sulphinyl groups or sulphonyl groups may also be present; the chain may moreover be substituted with one or more halogen atoms or with one or more optionally substituted' phenyl groups, heteroaryl groups or heterocyclic groups; if the chain comprises a nitrogen atom, this is substituted with at least one group R_s which is an optionally substituted phenyl group or an alkyl group, cycloalkyl group, hydroxyalkyl group;

R₁ and R₂ may be alkyl, cycloalkyl, optionally substituted phenyl or heteroaryl, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, mono- or dialkylamino, mono- or diarylamino, hydroxyl, amino, alkyl-, alkoxy- or amino, or mono- or dialkylaminocarbonyl, nitro, cyano, halogen, trifluoromethyl, trifluoromethoxy, alkyl- or amino- or mono- or dialkylaminosulphonyl; R2 may moreover be an oxo group or thioxo group; m has the value 0-3 and p has the value 0-2; and

R₃ is an alkyl group and n has the value 0-2, or an acid addition salt thereof for the manufacture of a medicament having psychotropic activity.

2. Use as claimed in claim 1 characterized in'that a compound of the formula (1), in which:

A forms together with the two carbon atoms of the phenyl group an entirely or partly unsaturated ring consisting of 5-atoms, which ring comprises at least one oxygen atom;

B is straight, branched or cyclic alkyl, alkenyl, alkynyl, alkoxy- or hydroxyalkyl, aryl- or heteroarylalkyl, or a group of the formula ―D―NR₅―CO―R₆, in which D is an optionally branched alkyl chain having at most 8 carbon atoms, R_s has the above meaning, and R₆ is alkyl, cycloalkyl, a phenyl group substituted with a group R₁, in which R₁ has the above-mentioned meaning, a saturated or non-saturated heterocyclic group, or R₅ and R₆ together with the group ―NR₅―CO― form a heterocyclic system;

R₁ and R₂ are alkyl, alkoxy, hydroxyl, nitro, cyano, halogen, trifluoromethyl, on the understanding that R₁ is in the meta- and/or para-position in relation to the piperazine group;

m and p have the value 0-2; and

n is 0, or an acid addition salt thereof is used as the active component.

3. Use according to claim 1, characterized in that:

a) I-(benzo[b]furan-7-yl)-4-methylpiperazine;

b) 1-[4-fluoro(benzo[b]furan-7-yl)]-4-methylpiperazine;

c) 1-[5-fluoro(benzo[b]furan-7-yl)]-4-methylpiperazine;

d) 1-(benzo[b]furan-7-yl)-4-(2-hydroxyethyl)piperazine;

e) 1-(benzo[b]furan-7-yl)-4-propylpiperazine;

f) 1-(benzo[b]furan-7-yl)-4-isopropylpiperazine;

g) 1-[5-fluoro(benzo[b]furan-7-yl)]-4-isopropylpiperazine;

h) 1-(benzdioxol-4-yl)-4-isopropylpiperazine;

i) 1-(benzo[b]furan-7-yl)-4-allylpiperazine;

j) 1-(benzo[b]furan-7-yl)-4-propargylpiperazine;

k) 1-[4-fluoro(benzo[b]furan-7-yl)]-4-propagylpiperazine;

I) 1-(benzdioxol-4-yl)-4-propargylpiperazine;

m) 1-(benzo[b]furan-7-yl)-4-isobutylpiperazine;

n) 1-(benzo[b]furan-7-yl)-4-cyclopropylmethylpiperazine;

o) I-(benzo[b]furan-7-yl)-4-pentylpiperazine;

p) 1-(benzo[b]furan-7-yl)-4-[2-(2-furyl)ethyl]piperazine;

q) 1-(benzo[b]furan-7-yl)-4-(4-chlorobenzyl)piperazine;

r) 1-(benzo[b]furan-7-yl)-4-(2-phenylethyl)piperazine;

s) 1-(benzo(b]furan-7-yl)-4-(2-[N-(acetyl)-N-(methyl)amino]ethyl]piperazine;

t) 1-(benzo[b]furan-7-yl)-4-[2-[N-(pyrrolidin-2-onyl)]ethyl]piperazine;

u) 1-(benzo[b]furan-7-yl)-4-[2-(N-succinimidyl)ethyl]piperazine;

v) 1-(benzo[b]furan-7-yl)4-[2-[N-(oxazolidin-2-onyl)ethyl]]piperazine;

w) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-chlorobenzoyl)-N-(methyl)amino]ethyl]piperazine;

x) I-benzo[b]furan-7-yl)-4-[2-[N-(4-cyanobenzoyl)-N-(methylamino]ethyl]piperazine;

y) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-nitrobenzoyl)-N-(methyl)amino]ethyl]piperazine;

z) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-methoxybenzoyl)-N-(methyl)amino]ethyl]piperazine;

aa) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-(methyl)amino]ethyl]piperazine;

bb) 1-[4-fluoro(benzo(b]furan-7-yl)]-4-[2-[N-(4-isopropylbenzoyl)-N-(methyl)amino]ethyl]piperazine;

cc) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl-N-(2-hydroxyethyl)amino]ethyl]piperazine;

dd) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-propyl)amino]ethyl]piperazine;

ee) 1-(benzo[b]furan-7-yl)-4-[[N-methyl-5-(4-fluorophenyl)pyrrol-2-yl]methyl]piperazine;

ff) 1-(benzo[b]furan-7-yl)-4-(acetylmethyl)piperazine, and acid addition salts thereof are used.

4. Compounds of the formula (1) having psychotropic properties, wherein A, B, R₁―R₃, m, n and p have the meanings given in claim 1, and acid addition salts thereof, with the exception of the compounds wherein A forms together with the two carbon atoms of the phenyl group a completely are partly unsaturated 5- or 6-membered ring which contains a nitrogen atom in the meta- or ortho-position in relation to the piperazine group as the only hetero atom, R, is halogen, nitro or lower alkoxy, R₂ is lower alkyl or an oxo group, n is 0, p is 0 or 1, m has the value 0-2, and B has the above meaning.

5. Compounds of the formula (1), wherein A, B, R,-R₃, m, n and p have the meanings given in claim 2 and acid addition salts thereof.

6. Compound selected from the group consisting of:

a) 1-(benzo[b]furan-7-yl)-4-methylpiperazine;

b) 1-[4-fluoro(benzo[b]furan-7-yl)]-4-methylpiperazine;

c) 1-[5-fluoro(benzo[b]furan-7-yl)]-4-methylpiperazine;

d) 1-(benzo[b]furan-7-yl)-4-(2-hydroxyethyl)piperazine;

e) 1-(benzo[b]furan-7-yl)-4-propylpiperazine;

f) 1-(benzo[b]furan-7-yl)-4-isopropylpiperazine;

g) 1-[5-fluoro(benzo[b]furan-7-yl)]-4-isopropylpiperazine;

h) 1-(benzdioxol-4-yl)-4-isopropylpiperazine;

i) 1-(benzo[b]furan-7-yl)-4-allylpiperazine;

j) 1-(benzo[b]furan-7-yl)-4-propargylpiperazine;

k) 1-[4-fluoro(benzo[b]furan-7-yl)]-4-propargylpiperazine;

I) 1-(benzdioxol-4-yl)-4-propargylpiperazine;

m) 1-(benzo[b]furan-7-yl)-4-isobutylpiperazine;

n) 1-(benzo[b]furan-7-yl)-4-cyclopropylmethylpiperazine;

o) 1-(benzo[b]furan-7-yl)-4-pentylpiperazine;

p) 1-(benzo[b]furan-7-yl)-4-[2-(2-furyl)ethyl]piperazine;

q) 1-(benzo[b]furan-7-yl)-4-(4-chlorobenzyl)piperazine;

r) 1-(benzo[b]furan-7-yl)-4-(2-phenylethyl)piperazine;

s) 1-(benzo[b]furan-7-yl)-4-[2-[N-(acetyl)-N-(methyl)amino]ethyl]piperazine;

t) 1-(benzo[b]furan-7-yl)-4-[2-[N-(pyrrolidin-2-onyl)]ethyl]piperazine;

u) 1-(benzo[b]furan-7-yl)-4-[2-(N-succinimidyl)ethyl]piperazine;

v) 1-(benzo[b]furan-7-yl)4-[2-[N-(oxazolidin-2-onyl)ethyl]]piperazine;

w) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-chlorobenzoyl)-N-(methyl)amino]ethyl]piperazine;

x) 1-benzo[b]furan-7-yl)-4-[2-[N-(4-cyanobenzoyl)-N-(methylamino]ethyl]piperazine;

y) 1-〈benzo[b]furan-7-yl〉-4-[2-[N-(4-nitrobenzoyl〉-N-(methyl)amino]ethyl]piperazine;

z) 1-〈benzo[b]furan-7-yl)-4-[2-[N-(4-methoxybenzoy))-N-(methy))amino]ethyl]piperazine; -

aa) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-(methyl)amino]ethyl]piperazine;

bb) 1-[4-fluoro(benzo[b]furan-7-yl)]-4-[2-[N-(4-isopropylbenzoyl)-N-(methyl)amino]ethyl]piperazine;

cc) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl-N-(2-hydroxyethyl)amino]ethyl]piperazine;

dd) 1-(benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-propyl)amino]ethyl]piperazine;

ee) 1-(benzo[b]furan-7-yl)-4-[[N-methyl-5-(4-fluorophenyl)pyrrol-2-yl]methyl]piperazine;

ff) 1-(benzo[b]furan-7-yl)-4-(acetylmethyl)piperazine.

7. A method of preparing bicyclic heteroarylpiperazine derivatives in a manner known forthe synthesis of analogous compounds, characterized in that compounds of formula (1), in which A, B, R₁―R₃, m, n and p have the meanings given in Claim 4, and acid addition salts are prepared by reaction of a compound of formula 2

with a compound of formula L-B, in which A, B, R₁-R₃, m, n and p have the above-mentioned meanings, and L is a leaving group.

8. A method as claimed in claim 7, characterized in that compounds of the formula (1), in which the symbols have the meanings given in claim 1 are prepared by reacting a compound of formula (2), with a compound of formula B'=O in the presence of a reducing agent, in which formulae A, R₁-R₃, m, n and p have the above meaning and B' after reaction gives a group B of the above meaning.

9. A method as claimed in claim 7, characterized in that compounds of formula (1), in which A, R₁―R₃, m, n and p have the meanings given in Claim 1, and B is a group of the formula D―NR₅―CO―R₆, in which D, R_s and R₆ have the meanings given in Claim 2, with the proviso that R₅ cannot be phenyl, and acid addition salts and prodrugs thereof, are prepared by converting the corresponding compound of formula 3

with a compound of the formula L-R_s, in which A, D, R₁-R₃, R_s, R₆, m, n and p have the above-mentioned meanings, and L is a leaving group.

10. A method as claimed in Claim 7, characterized in that a compound of formula 1 is prepared, in which A, R₁-C₃, m, n and p have the meanings given in Claim 1 and B is a group of the formula ―D―NR₅―CO―R₆, in which D, R_s and R₆ have the meanings given in Claim 2, by converting a compound of formula 4

with a compound E-CO-R₆, in which E is a leaving group.

11. A method as claimed in Claim 7, characterized in that a compound of formula 1 is prepared by reduction of a compound of the formula (1), wherein A, R₁―R₃, n, m and p have the meaning given in Claim 1, and B contains a carbonyl group which is attached to the piperazine nitrogen atom.

12. A method as claimed in claim 7, characterized in that a precursor of a compound of the formula (1) is hydrogenated in a way known perse, or is reacted with a nucleophile containing a hetereo atom in a way known perse resulting in a bond between a carbon atom and a hetero atom.

13. A method as claimed in Claim 7, characterized in that a compound of formula 1 is prepared in which at least one of the groups B, R₁, R₂, R₄, or R₅ is a hydroxyalkyl group, or in which B contains a group NH-R₅, by removing, as the last step, a protective group or protective groups in a manner know perse.

Ansprüche

1. Verwendung einer Verbindung der Formel (I)

worin

A zusammen mit den zwei Kohlenstoffatomen der Phenylgruppe eine vollständig oder teilweise ungesättigte cyclische Gruppe mit 5 bis 7 Ringatomen mit 1 bis 3 Heteroatomen aus der Gruppe O, S und N im Ring bildet, mit der Maßgabe, daß die Summe der Zahl von Sauerstoffatomen und Schwefelatomen höchstens 2 beträgt und daß die Stickstoffatome im Ring mit einer Gruppe R₄ substituiert sein können, die Wasserstoff, Alkyl, Hydroxyalkyl oder Acyl sein kann;

B eine gegebenenfalls verzweigte oder cyclische, gesättigte oder (poly)ungesättigte aliphatische Kette ist, die ein oder mehrere Atome aus der Gruppe O und N in der Kette oder endständig aufweisen kann und in der auch Carbonylgruppen, Thiocarbonylgruppen, Sulfinylgruppen oder Sulfonylgruppen vorhanden sein können; die Kette außerdem mit einem oder mehreren Halogenatomen oder mit einer oder mehreren gegebenenfalls substituierten Phenylgruppen, Heteroarylgruppen oder heterocyclischen Gruppen substituiert sein kann; wenn die Kette ein Stickstoffatom umfaßt, dieses mit mindestens einer Gruppe R_s substituiert ist, die eine gegebenenfalls substituierte Phenylgruppe oder eine Alkylgruppe, Cycloalkylgruppe oder Hydroxyalkylgruppe ist;

R₁ und R₂ Alkyl, Cycloalkyl, gegebenenfalls substituiertes Phenyl oder Heteroaryl, Hydroxyalkyl, Alkoxyalkyl, Alkoxy, Aryloxy, Alkylthio, Arylthio, Mono- oder Dialkylamino, Mono- oder Diarylamino, Hydroxyl, Amino, Alkyl-, Alkoxy- oder Amino- oder Mono- oder Dialkylaminocarbonyl, Nitro, Cyano, Halogen, Trifluormethyl, Trifluormethoxy, Alkyl- oder Amino- oder Mono- oder Dialkylaminosulfonyl sein können und R₂ außerdem eine Oxogruppe oder eine Thioxogruppe sein kann; m den Wert Null bis 3 hat, p den Wert Null bis 2 hat,

R₃ eine Alkylgruppe ist und n den Wert Null bis 2 hat, oder ein Säureadditionssalz hievon zur Herstellung eines Medikaments mit psychotroper Wirksamkeit.

2. Verwendung, wie in Anspruch 1 beansprucht, dadurch gekennzeichnet, daß eine Verbindung der Formel (I), worin

A zusammen mit den zwei Kohlenstoffatomen der Phenylgruppe einen zur Gänze oder teilweise ungesättigten Ring bestehend aus 5 Atomen, welcher Ring mindestens ein Sauerstoffatom aufweist, bildet,

B gerades, verzweigtes oder cyclisches Alkyl, Alkenyl, Alkinyl, Alkoxy- oder Hydroxyalkyl, Aryl- oder Heteroarylalkyl oder eine Gruppe der Formel ―D―NR₅―CO―R₆ ist, worin D eine gegebenenfalls verzweigte Alkylgruppe mit höchstens 8 Kohlenstoffatomen bedeutet, R_s die obige Bedeutung hat und R₆ Alkyl, Cycloalkyl, eine mit einer Gruppe R, substituierte Phenylgruppe, wobei R, die oben angegebene Bedeutung hat, eine gesättigte oder nichtgesättigte heterocyclische Gruppe darstellt oder R_s und R₆ zusammen mit der Gruppe -NR₅-CO- ein heterocyclisches System bilden,

R, und R₂ Alkyl, Alkoxy, Hydroxyl, Nitro, Cyano, Halogen oder Trifluormethyl bedeuten, mit der Maßgabe, daß R, in bezug auf die Piperazingruppe in m- und/oder p-Stellung ist,

m und p den Wert Null bis 2 haben und

n Null ist, oder ein Säureadditionssalz hievon als aktiver Bestandteil verwendet wird.

3. Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß

a) 1-(Benzo[b]furan-7-yl)-4-methylpiperazin;

b) 1-[4-Fluor(benzo[b]furan-7-yl)]-4-methylpiperazin;

c) 1-[5-Fluor(benzo[b]furan-7-yl)]-4-methylpiperazin;

d) 1-(Benzo[b]furan-7-yl)-4-(2-hydroxyäthyl)piperazin;

e) 1-(Benzo[b]furan-7-yl)-4-propylpiperazin;

f) 1-(Benzo[b]furan-7-yl)-4-isopropylpiperazin;

g) 1-[5-Fluor(benzo[b]furan-7-yl)]-4-isopropylpiperazin;

h) 1-(Benzdioxol-4-yl)-4-isopropylpiperazin;

i) 1-(Benzo[b]furan-7-yl)-4-allylpiperazin;

j) 1-(Benzo[b]furan-7-yl)-4-propargylpiperazin;

k) 1-[4-Fluor(benzo[b]furan-7-yl)]-4-propargylpiperazin;

I) 1-(Benzdioxol-4-yl)-4-propargylpiperazin;

m) 1-(Benzo[b]furan-7-yl)-4-isobutylpiperazin;

n) 1-(Benzo[b]furan-7-yl)-4-cyclopropylmethylpiperazin;

o) 1-(Benzo[b]furan-7-yl)-4-pentylpiperazin;

p) 1-(Benzo[b]furan-7-yl)-4-[2-(2-furyl)äthyl]piperazin;

q) 1-(Benzo[b]furan-7-yl)-4-(4-chlorbenzyl)piperazin;

r) 1-(Benzo[b]furan-7-yl)-4-(2-phenyläthyl)piperazin;

s) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(acetyl)-N-(methyl)amino]äthyl]piperazin;

t) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(pyrrolidon-2-onyl)]äthyl]piperazin;

u) 1-(Benzo[b]furan-7-yl)-4-[2-(N-succinimidyl)äthyl]piperazin;

v) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(oxazolidin-2-onyl)äthyl]]piperazin;

w) 1-(Benzo[bjfuran-7-yl)-4-[2-[N-(4-chlorbenzoyl)-N-(methyl)amino]äthyl]piperazin;

x) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(4-cyanobenzoyl)-N-(methyl)amino]äthyl]piperazin;

y) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(4-nitrobenzoyl)-N-(methyl)amino]äthyl]piperazin;

z) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(4-methoxybenzoyl)-N-(methyl)amino]äthyl]piperazin;

aa) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-(methyl)amino]äthyl]piperazin;

bb) 1-[4-Fluor(benzo[b]furan-7-yl)]-4-[2-[N-(4-isopropylbenzoyl)-N-(methyl)amino]äthyl]piperazin;

cc) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-(2-(hydroxyäthyl)amino]äthyl]piperazin;

dd) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-(propyl)amino]äthyl]piperazin;

ee) 1-(Benzo[b]furan-7-yl)-4-[[N-methyl-5-(4-fluorphenyl)pyrrol-2-yl]methyl]piperazin;

ff) 1-(Benzo[b]furan-7-yl)-4-(acetylmethyl)piperazin und Säureadditionssalze hievon verwendet werden.

4. Verbindungen der Formel (I) mit psychotropen Eigenschaften, worin A, B, R₁ bis R₃, m, n und p die in Anspruch 1 angegebenen Bedeutungen haben, und deren Säureadditionssalze, ausgenommen die Verbindungen, worin A zusammen mit den beiden Kohlenstoffatomen der Phenylgruppe einen vollständig oder teilweise ungesättigten 5- oder 6-gliedrigen Ring bildet, der in m- oder o-Stellung in bezug auf die Piperazingruppe ein Stickstoffatom als einziges Heteroatom enthält, R₁ Halogen, Nitro oder nied.Alkoxy bedeutet, R₂ nied.Alkyl oder eine Oxogruppe darstellt, n Null ist, p Null oder 1 ist, m den Wert Null bis 2 hat und B die oben angegebene Bedeutung besitzt.

5. Verbindungen der Formel (I), worin A, B, R₁ bis R₃, m, n und p die in Anspruch 2 angegebenen Bedeutungen haben, und deren Säureadditionssalze.

6. Verbindung ausgewählt aus der Gruppe bestehend aus:

a) 1-(Benzo[b]furan-7-yl)-4-methylpiperazin;

b) 1-[4-Fluor(benzo[blfuran-7-yl)l-4-methylpiperazin;

c) 1-[5-Fluor(benzo[b]furan-7-yl)]-4-methylpiperazin;

d) 1-(Benzo[b]furan-7-yl)-4-(2-hydroxyäthyl)piperazin;

e) 1-(Benzo[b]furan-7-yl)-4-propylpiperazin;

f) 1-(Benzo[b]furan-7-yl)-4-isopropylpiperazin;

g) 1-[5-Fluor(benzo[b]furan-7-yl)]-4-isopropylpiperazin;

h) 1-(Benzdioxol-4-yl)-4-isopropylpiperazin;

i) 1-(Benzo[b]furan-7-yl)-4-allylpiperazin;

j) 1-(Benzo[b]furan-7-y))-4-propargyipiperazin;

k) 1-[4-Fluor(benzo[b]furan-7-yl)]-4-propargylpiperazin;

I) 1-(Benzdioxol-4-yl)-4-propargylpiperazin;

m) 1-(Benzo[b]furan-7-yl)-4-isobutylpiperazin;

n) 1-(Benzo[b]furan-7-yl)-4-cyctopropylmethylpiperazin;

o) 1-(Benzo[b]furan-7-yl)-4-pentylpiperazin;

p) 1-(Benzo[b]furan-7-yl)-4-[2-(2-furyl)äthyl]piperazin;

q) 1-(Benzo[b]furan-7-yl)-4-(4-chlorbenzyl)piperazin;

r) 1-(Benzo[b]furan-7-yl)-4-(2-phenyläthyl)piperazin;

s) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(acetyl)-N-(methyl)amino]äthyl]piperazin;

t) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(pyrrolidon-2-onyl)]äthyl]piperazin;

u) 1-(Benzo[b]furan-7-yl)-4-[2-(N-succinimidyl)äthyl]piperazin;

v) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(oxazolidin-2-onyl)äthyl]]piperazin;

w) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(4-chlorbenzoyl)-N-(methyl)amino]äthyl]piperazin;

x) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(4-cyanobenzoyl)-N-(methyl)amino]äthyl]piperazin;

y) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(4-nitrobenzoyl)-N-(methyl)amino]äthyl]piperazin;

z) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(4-methoxybenzoyl)-N-(methyl)amino]äthyl]piperazin;

aa) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-(methyl)amino]äthyl]piperazin;

bb) 1-[4-Fluor(benzo[b]furan-7-yl)]-4-[2-[N-(4-isöpropylbenzoyl)-N-(methyl)amino]äthyl]piperazin;

cc) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-(2-(hydroxyäthyl)amino]äthyl]piperazin;

dd) 1-(Benzo[b]furan-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-(propyl)amino]äthyl]piperazin;

ee) 1-(Benzo[b]furan-7-yl)-4-[[N-methyl-5-(4-fluorphenyl)pyrrol-2-yl]methyl]piperazin;

ff) 1-(Benzo[b]furan-7-yl)-4-(acetylmethyl)piperazin.

7. Verfahren zum Herstellen von bicyclischen Heteroarylpiperazinderivaten auf eine für die Synthese von analogen Verbindungen bekannte Weise, dadurch gekennzeichnet, daß Verbindungen der Formel (1), worin A, B, R₁ bis R₃, m, n und p die in Anspruch 4 angegebenen Bedeutungen haben, und Säureadditionssalze durch Umsetzen einer Verbindung der Formel (11)

mit einer Verbindung der Formel L-B, worin A, B, R₁ bis R₃, m, n und p die oben angegebenen Bedeutungen haben und L eine abspaltbare Gruppe darstellt, hergestellt werden.

8. Verfahren nach Anspruch 7, dadurch gekennzeichnet, daß Verbindungen der Formel (1), worin die Symbole die in Anspruch 1 angegebenen Bedeutungen haben, durch Umsetzen einer Verbindung der Formel (II) mit einer Verbindung der Formel B'=O in Anwesenheit eines Reduktionsmittels, in welchen Formeln A, R₁ bis R₃, m, n und p die obige Bedeutung haben und B' nach Reaktion eine Gruppe B mit der obigen Bedeutung ergibt, hergestellt werden.

9. Verfahren, wie in Anspruch 7 beansprucht, dadurch gekennzeichnet, daß Verbindungen der Formel (I), worin A, R₁ bis R₃, m, n und p die in Anspruch 1 angegebenen Bedeutungen haben und B eine Gruppe der Formel D―NR₅―CO―R₆ ist, worin D, R₅ und R_e die in Anspruch 2 angegebenen Bedeutungen haben, mit der Maßgabe, daß R_s nicht Phenyl sein kann, und Säureadditionssalze und Arzneimittelvorläufer hievon durch Überführen der entsprechenden Verbindung der Formel (III)

mit einer Verbindung der Formel L-R_s, worin A, D, R₁ bis R₃, R₅, R_e, m, n und p die oben angegebenen Bedeutungen haben und L eine abspaltbare Gruppe ist, hergestellt werden.

10. Verfahren, wie in Anspruch 7 beansprucht, dadurch gekennzeichnet, daß eine Verbindung der Formel (I), worin A, R₁ bis R₃, m, n und p die in Anspruch 1 angegebenen Bedeutungen haben und B eine Gruppe der Formel D―NR₅―CO―R₆ ist, worin D, R_s und R₆ die in Anspruch 2 angegebenen Bedeutungen haben, durch Überführen einer Verbindung der Formel (IV)

mit einer Verbindung der Formel E―CO―R₆, worin E eine abspaltbare Gruppe ist, hergestellt werden.

11. Verfahren, wie in Anspruch 7 beansprucht, dadurch gekennzeichnet, daß eine Verbindung der Formel (I) durch Reduktion einer Verbindung der Formel (I), worin A, R₁ bis R₃, n, m und p die in Anspruch 1 angegebene Bedeutung haben und B eine Carbonylgruppe enthält, die an das Piperazinstickstoffatom gebunden ist, hergestellt wird.

12. Verfahren, wie in Anspruch 7 beansprucht, dadurch gekennzeichnet, daß ein Vorläufer einer Verbindung der Formel (I) in an sich bekannter Weise hydriert oder mit einem ein Heteroatom enthaltenden Nukleophil in an sich bekannter Weise umgesetzt wird, wobei eine Bindung zwischen einem Kohlenstoffatom und einem Heteroatom erhalten wird.

13. Verfahren, wie in Anspruch 7 beansprucht, dadurch gekennzeichnet, daß eine Verbindung der Formel (1), worin mindestens eine der Gruppen, B, R₁, R₂, R₄ oder R₅ eine Hydroxyalkylgruppe bedeutet oder worin B eine Gruppe NH―R₅ enthält, durch Entfernen einer Schutzgruppe oder von Schutzgruppen auf an sich bekannte Weise als letzter Schritt hergestellt wird.

Revendications

1. Utilisation d'un composé de formule 1

dans laquelle:

A, avec les deux atomes de carbone du groupe phényle, forme un groupe cyclique entièrement ou partiellement insaturé comportant 5-7 atomes sur le noyau avec, dans le noyau, 1-3 hétéroatomes du groupe O, S et N, à condition que la somme du nombre d'atomes d'oxygène et d'atomes de soufre soit au plus égale à 2 et que les atomes d'azote dans le noyau puissent être substitués par un groupe R₄ qui peut un hydrogène, un groupe alkyle, hydroxyalkyle ou acyle;

B est une chaîne aliphatique saturée ou (poly)insaturée, éventuellement ramifiée ou cyclique, qui peut comprendre un ou plusieurs atomes du groupe O et N dans la chaîne ou en position terminale et dans laquelle peuvent également être présents des groupes carbonyle, des groupes thiocarbonyle, des groupes sulfinyle ou des groupes sulfonyle; la chaîne peut en outre être substituée par un ou plusieurs atomes d'halogène ou par ou plusieurs groupes phényle, groupes hétéroaryle ou groupes hétérocycliques éventuellement substitués; si la chaîne comprend un atome d'azote, celui-ci est substitué par au moins un groupe R₅ qui est un groupe phényle éventuellement substitué ou un groupe alkyle, un groupe cycloalkyle, un groupe hydroxyalkyle;

R, et R₂ peuvent être des groupes alkyle, cycloalkyle, phényle ou hétéroaryle éventuellement substitués, hydroxyalkyle, alcoxyalkyle, alcoxy, aryloxy, alkylthio, arylthio, mono- ou dialkylamino, mono-ou diarylamino, hydroxyle, amino, alkyl-, alcoxy- ou amino, ou mono- ou dialkylaminocarbonyle, nitro, cyano, halogéno, trifluorométhyle, trifluorométhoxy, alkyl- ou amino- ou mono- ou dialkylaminosulfonyle; R₂ peut en outre être un groupe oxo ou un groupe thioxo; m a la valeur 0-3 et p a la valeur 0,2; et

R₃ est un groupe alkyle et n a la valeur 0-2, ou d'un de ses sels d'addition d'acide pour fabriquer un médicament ayant une activité psychotrope.

2. Utilisation selon la revendication 1, caractérisé en ce que l'on utilise, comme constituant actif, un composé de formule (1), dans laquelle:

A forme, avec les deux atomes de carbone du groupe phényle, un noyau entièrement ou partiellement insaturé constitué de 5 atomnes, ce noyau comprenant au moins un atome d'oxygène;

B est un groupe linéaire, ramifié ou cyclique, alkyle, alcényle, alcynyle, alcoxy- ou hydroxyalkyle, aryl-ou hétéroarylalkyle, ou un groupe de formule ―D―NR₅―CO―R₆, dans lequel D est une chaîne alkyle éventuellement ramifiée comportant au plus 8 atomes de carbone, R₅ a la signification ci-dessus et R_e est un groupe alkyle, cycloalkyle, phényle substitué par un groupe R₁, dans lequel R, a la signification susmentionnée, un groupe hétérocyclique saturé ou non saturé, ou R₅ et R₆ forment, conjointement avec le groupe -NR₅-CO-, un système hétérocyclique;

R, et R₂ sont des groupes alkyle, alcoxy, hydroxyle, nitro, cyano, halogéno, trifluorométhyle, étant entendu que R, est en position méta et/ou para relativement au groupe pipérazine;

m et p ont la valeur 0-2; et

n est nul, ou un de ses sels d'addition d'acide.

3. Utilisation selon la revendication 1, caractérisée en ce que l'on utilise:

a) la 1-(benzo[b]furanne-7-yl)-4-méthylpipérazine;

b) la 1-[4-fluoro-(benzo[b]furanne-7-yl)-4-méthylpipérazine;

c) la 1-[5-fluoro-(benzo[b]furanne-7-yl)-4-méthylpipérazine;

d) la 1-(benzo[b]furanne-7-yl)-4-(2-hydroxyéthyl)pipérazine;

e) la 1-(benzo[b]furanne-7-yl)-4-propylpipérazine;

f) la 1-(benzo[b]furanne-7-yl)-4-isopropylpipérazine;

g) la 1-[5-fluoro-(benzo[b]furanne-7-yl)]-4-isopropylpipérazine;

h) la 1-(benzdioxol-4-yl)-4-isopropylpipérazine;

i) la 1-(benzo[b]furanne-7-yl)-4-allylpipérazine;

j) la 1-(benzo[b]furanne-7-yl)-4-propargylpipérazine;

k) la 1-[4-fluoro(benzo[b]furanne-7-yl)-4-propargylpipérazine;

I) la 1-(benzdioxol-4-yl)-4-propargylpipérazine;

m) la 1-(benzo[b]furanne-7-yl)-4-isobutylpipérazine;

n) la 1-(benzo[b]furanne-7-yl)-4-cyclopropylméthylpipérazine;

o) la 1-(benzo(b]furanne-7-yl)-4-pentylpipérazine;

p) la 1-(benzo[b]furanne-7-yl)-4-[2-(2-furyl)éthyl]pipérazine;

q) la 1-(benzo[b]furanne-7-yl)-4-(4-chlorobenzyl)pipérazine;

r) la 1-(benzo[b]furanne-7-yl)-4-(2-phényléthyl)pipérazine;

s) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(acétyl)-N-(méthyl)amino]éthyl]pipérazine;

t) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(pyrrolidine-2-onyl)]éthyl]pipérazine;

u) la 1-(benzo[b]furanne-7-yl)-4-[2-(N-succinimidyl)éthyl]pipérazine;

v) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(oxazolidine-2-onyl)éthyl]]pipérazine;

w) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-chlorobenzoyl)-N-(méthyl)amino]éthyl]pipérazine;

x) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-cyanobenzoyl)-N-(méthylamino)éthyl]pipérazine;

y) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-nitrobenzoyl)-N-(méthyl)amino]éthyl]pipérazine;

z) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-méthoxybenzoyl)-N-(méthyl)amino]éthyl]pipérazine;

aa) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-(méthyl)amino]éthyl]pipérazine;

bb) la 1-[4-fluoro(benzo[b]furanne-7-yl)]-4-[2-(N-(4-isopropylbenzoyl)-N-(méthyl)amino]éthyl]-pipérazine;

cc) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-isopropylbenzoyl-N-(2-hydroxyéthyl)amino]éthyl]pipérazine;

dd) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-isopropylbenzoyl-N-propyl)amino]éthyl]pipérazine;

ee) la 1-(benzo[b]furanne-7-yl)-4-[[N-méthyl-5-(4-fluorophényl)-pyrrole-2-yl]méthyl]pipérazine;

ff) la 1-(benzo[b]furanne-7-yl)-4-(acétylméthyl)pipérazine, et leurs sels d'addition d'acide.

4. Composés de formule (1) ayant des propriétés psychotropes, dans lesquels A, B, R₁―R₃, m, n et p ont les significations indiquées dans la revendication 1, et leurs sels d'addition d'acide, à l'exception des composés dans lesquels A forme, avec les 2 atomes de carbone du groupe phényle, un noyau à 5 ou 6 chaînons entièrement ou partiellement insaturé qui contient un atome d'azote en position méta ou ortho par rapport au groupe pipérazine comme seul hétéroatome, R₁ est un halogène, un groupe nitro ou alcoxy inférieur, R₂ est un groupe alkyle inférieur ou un groupe oxo, n est nul, p est nul ou égal à 1, m a la valeur 0-2 et B a la signification ci-dessus.

5. Composés de formule (1), dans lesquels A, B, R₁―R₃, m, n et p ont les significations indiquées dans la revendication 2 et leurs sels d'addition d'acide.

6. Composés choisis dans le groupe constitué par:

a) la 1-(benzo[b]furanne-7-yl)-4-méthylpipérazine;

b) la 1-[4-fluoro-(benzo[b]furanne-7-yl)-4-méthylpipérazine;

c) la 1-[5-fluoro-(benzo[b]furanne-7-yl)-4-méthylpipérazine;

d) la 1-(benzo[b]furanne-7-yl)-4-(2-hydroxyéthyl)pipérazine;

e) la 1-(benzo[b]furanne-7-yl)-4-propylpipérazine;

f) la 1-(benzo[b]furanne-7-yl)-4-isopropylpipérazine;

g) la 1-[5-fluoro-(benzo[b]furanne-7-yl)]-4-isopropylpipérazine;

h) la 1-(benzdioxol-4-yl)-4-isopropylpipérazine;

i) la 1-(benzo[b]furanne-7-yl)-4-allylpipérazine;

j) la 1-(benzo[b]furanne-7-yl)-4-propargylpipérazine;

k) la 1-[4-fluoro(benzo[b]furanne-7-yl)-4-propargylpipérazine;

I) la 1-(benzdioxol-4-yl)-4-propargylpipérazine;

m) la 1-(benzo[b]furanne-7-yl)-4-isobutylpipérazine;

n) la 1-(benzo[b]furanne-7-yl)-4-cyclopropylméthylpipérazine;

o) la 1-(benzo[b]furanne-7-yl)-4-pentylpipérazine;

p) la 1-(benzo[b]furanne-7-yl)-4-[2-(2-furyl)éthyl]pipérazine;

q) la 1-(benzo[b]furanne-7-yl)-4-(4-chlorobenzyl)pipérazine;

r) la 1-(benzo[b]furanne-7-yl)-4-(2-phényléthyl)pipérazine;

s) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(acétyl)-N-(méthyl)amino]éthyl]pipérazine;

t) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(pyrrolidine-2-onyl)]éthyl]pipérazine;

u) la 1-(benzo[b]furanne-7-yl)-4-[2-(N-succinimidyl)éthyl]pipérazine;

v) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(oxazolidine-2-onyl)éthyl]]pipérazine;

w) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-chlorobenzoyl)-N-(méthyl)amino]éthyl]pipérazine;

x) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-cyanobenzoyl)-N-(méthylamino)éthyl]pipérazine;

y) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-nitrobenzoyl)-N-(méthyl)amino]éthyl]pipérazine;

z) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-méthoxybenzoyl)-N-(méthyl)amino]éthyl]pipérazine;

aa) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-isopropylbenzoyl)-N-(méthyl)amino]éthyl]pipérazine;

bb) la 1-[4-fluoro(benzo[b]furanne-7-yl)]-4-(2-[N-(4-isopropylbenzoyl)-N-(méthyl)amino]éthyl]-pipérazine;

cc) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-isopropylbenzoyl-N-(2-hydroxyéthyl)amino]éthyl]pipérazine;

dd) la 1-(benzo[b]furanne-7-yl)-4-[2-[N-(4-isopropylbenzoyl-N-propyl)amino]éthyl]pipérazine;

ee) la 1-(benzo[b]furanne-7-yl)-4-[[N-méthyl-5-(4-fluorophényl)-pyrrole-2-yl]méthyl]pipérazine;

ff) la 1-(benzo[b]furanne-7-yl)-4-(acétylméthyl)pipérazine, et de ses sels d'addition d'acide.

7. Procédé de préparation de dérivés hétéroarylpipérazines bicycliques d'une manière connue pour la synthèse des composés analogues, caractérisé en ce que l'on prépare les composés de formule (1), dans laquelle A, B, R_I-R₃, m, n etp ont les significations indiquées dans la revendication 4, et des sels d'addition d'acide, en faisant réagir un composé de formule 2

avec un composé de formule L-B, dans laquelle A, B, R_l-R₃, m, n etp ont les significations indiquées ci-dessus, et L est un groupe partant.

8. Procédé selon la revendication 7, caractérisé en ce que l'on prépare les composés de formule (1), dans laquelle les symboles ont les significations indiquées dans la revendication 1, en faisant réagir un composé de formule (2) avec un composé de formule B'=O, en présence d'un agent réducteur, formules dans lesquelles A, R,-R₃, m, n etp ont la signification ci-dessus et B', après la réaction, donne un groupe B ayant la signification ci-dessus.

9. Procédé selon la revendication 7, caractérisé en ce que l'on prépare les composés de formule (1), dans laquelle A, R₁―R₃, m, n et p ont les significations indiquées dans la revendication 1, et B est un groupe de formule D―NR₅―CO―R₆, dans laquelle D, R_s et R₆ ont les significations indiquées dans la revendication 2, à condition que R_s ne soit pas un groupe phényle, et leurs sels d'addition d'acide et leurs précurseurs de médicaments, en transformant les composés correspondants de formule 3

avec un composé de formule L-R_s, dans laquelle A, D, R₁-R₃, R₅, R₆, m, n et p ont les significations susmentionnées, et L est un groupe partant.

10. Procédé selon la revendication 7, caractérisé en ce que l'on prépare un composé de formule 1, dans laquelle A, R₁―R₃, m, n et p ont les significations indiquées dans la revendication 1 et B est un groupe de formule―D―RN₅―COR₆, dans laquelle D, R₅ et R₆ ont les significations indiquées dans la revendication 2, en transformant un composé de formule 4

avec un composé E―CO―R₆, dans lequel E est un groupe partant.

11. Procédé selon la revendication 7, caractérisé en ce que l'on prépare un composé de formule 1 en réduisant un composé de formule (1), dans laquelle A, R₁―R₃,n, m et p ont la signification indiquée dans la revendication 1, et B contient un groupe carbonyle qui est fixé à l'atome d'azote de la pipérazine.

12. Procédé selon la revendication 7, caractérisé en ce qu'un précurseur d'un composé de formule (1) est hydrogéné d'une manière connue en soi ou mis à réagir avec un nucléophile contenant un hétéroatome d'une manière connue en soi, pour conduire à une liaison entre un atome de carbone et un hétéroatome.

13. Procédé selon la revendication 7, caractérisé en ce que l'on prépare un composé de formule 1, dans laquelle l'un au moins des groupes B, R₁, R₂, R₄, ou R₅ est un groupe hydroxyalkyle, ou dans laquelle B contient un groupe NH-R_s, en éliminant, dans une dernière étape, un groupe protecteur ou des groupes protecteurs d'une manière connue en soi.